Manning threw for 260 yards and three touchdowns in the Rebels' 31-0 victory Thursday night in the 100th meeting between the Magnolia state rivals.
Mississippi (9-3 overall, 7-1 Southeastern Conference) remained in the SEC West title race and reached nine regular-season victories for the first time since 1990.
For Sherrill and Mississippi State (2-10, 1-7), the season ended with a sixth consecutive lopsided loss. Since the 60-year-old coach announced his retirement Oct. 17, the Bulldogs have been outscored, 267-57.
Sherrill received a long, loud standing ovation from Mississippi State fans when he was introduced before the game. But by the fourth quarter, most of the rain-soaked fans remaining in Scott Field were rooting for the Rebels.
Sherrill completed 13 seasons at Mississippi State with a 75-75-2 record, 8-27 over the final three.
Sherrill won over Bulldog fans by becoming the first Mississippi State coach in decades to consistently beat Mississippi, doing it seven times in his first 11 seasons.
In the end, he couldn't even do that. The Rebels won the Battle for the Golden Egg for the second consecutive season, a first during the Sherrill era.
The previous largest margin of victory for Mississippi against Sherrill's teams was 15. The shutout was the Rebels' first against the Bulldogs since 1971.
Manning and his Heisman Trophy candidacy took a beating in a loss to LSU on Saturday. The senior quarterback was often off-target against the Tigers but completed 19 of 27 passes against the Bulldogs during a steady rain.